Abstract: Background There are claims that second-generation antipsychotics produce fewer extrapyramidal side-effects (EPS) compared with first-generation drugs. Aims To compare the incidence of treatment-emergent EPS between second-generation antipsychotics and perphenazine in people with schizophrenia. Method Incidence analyses integrated data from standardised rating scales and documented use of concomitant medication or treatment discontinuation for EPS events. Mixed model analyses of change in rating scales from baseline were also conducted. Results There were no significant differences in incidence or change in rating scales for parkinsonism, dystonia, akathisia or tardive dyskinesia when comparing second-generation antipsychotics with perphenazine or comparing between second-generation antipsychotics. Secondary analyses revealed greater rates of concomitant antiparkinsonism medication among individuals on risperidone and lower rates among individuals on quetiapine, and lower rates of discontinuation because of parkinsonism among people on quetiapine and ziprasidone. There was a trend for a greater likelihood of concomitant medication for akathisia among individuals on risperidone and perphenazine. Conclusions The incidence of treatment-emergent EPS and change in EPS ratings indicated that there are no significant differences between second-generation antipsychotics and perphenazine or between second-generation antipsychotics in people with schizophrenia.

Abstract: Background: Drug-induced QTc prolongation is becoming increasingly important in oncology since novel therapies result in prolonged survival of cancer patients already predisposed to cardiotoxicity. Methods: We review the challenges of implementing the ICH E14 guidance in oncology and propose an integrated approach to QTc risk assessment of nonadjuvant anticancer agents (NAAs), with quantitative outcome criteria. Results: We recommend informed use of non-clinical cardiac safety pharmacology results, some degree of robust ECG assessments in early phase studies, a dedicated QTc study in cancer patients conducted at the appropriate time pre-, peri-, or post-approval (with the design and timing agreed upon with regulatory agencies), and ECG monitoring in late-phase studies commensurate with the outcome of previous QTc studies. Conclusion: The proposed approach would facilitate risk–benefit assessment for NAAs during clinical development and regulatory review, and enable adequate labeling for safe and effective...

Abstract: Polychlorinated biphenyls (PCBs) are ubiquitous industrial chemicals that persist in the environment and in human fatty tissue. PCBs are related to a class of compounds known as dioxins, specifically 2,3,7,8-TCDD (tetrachloro-dibenzodioxin), which has been implicated as a cause of altered sex ratio, especially in relation to paternal exposures. In the 1960's, serum specimens were collected from pregnant women participating in the Child Health and Development Study in the San Francisco Bay Area. The women were interviewed and their serum samples stored at -20°C. For this study, samples were thawed and a total of eleven PCBs were determined in 399 specimens. Secondary sex ratio, or sex ratio at birth, was evaluated as a function of maternal serum concentrations using log-binomial and logistic regression, controlling for hormonally active medications taken during pregnancy. The relative risk of a male birth decreased by 33% comparing women at the 90th percentile of total PCBs with women at the 10th percentile (RR = 0.67; 95% CI, 0.48–0.94; p = 0.02), or by approximately 7% for each 1 μg/L increase in total PCB concentration. Although some congener-specific associations with sex ratio were only marginally statistically significant, all nine PCB congeners with < 30% of samples below the LOQ showed the same direction of association, an improbable finding under the null hypothesis. Maternal exposure to PCBs may be detrimental to the success of male sperm or to the survival of male embryos. Findings could be due to contaminants, metabolites or PCBs themselves.

Abstract: In this article, we investigate the range of treatments prescribed to children with autism. The data suggest that approximately 58 percent of patients with a diagnosis of childhood autism receive some type of pharmaceutical treatment. The majority of those treated, 68 percent, receive only one pharmaceutical. The most commonly prescribed products are antipsychotics (66%), antidepressants (32%), and stimulants (17%). An expert commentary is included.

Abstract: Objective: To investigate the economic impact of micafungin (MICA) for treatment of invasive candidiasis and candidaemia (systemic Candida infections), a health economic analysis was conducted comparing MICA with liposomal amphotericin B (L-AMB).Research design and methods: The model was based on a phase III, randomised, double-blind, clinical trial which compared MICA with L-AMB. The model entailed a period of 14–20 weeks starting from initiation of treatment and was analysed from a German hospital perspective.Main outcome measures: The main outcome measures were defined as the percentage of patients achieving clinical and mycological response after initial treatment and who were alive at the end of the study (EOS), and the total treatment-associated costs over the study period.Results: The health economic analysis shows that with MICA, 52.9 % of patients are successfully treated and were alive at EOS compared to 49.1 % for L-AMB. In addition, MICA has, on average, lower treatment-associated cost...

Abstract: We examined the role of benzodiazepines in the treatment of anxiety by both psychiatrists and primary care physicians. Over the past year, 112.8 million prescriptions were filled for a benzodiazepine: 55 percent were prescribed by a primary care physician, 16 percent by a psychiatrist, and the remaining 29 percent of prescriptions by another type of specialty physician. Benzodiazepine monotherapy is much more common in the treatment of anxiety by primary care physicians (42%) than psychiatrists (22%). Even when both benzodiazepine monotherapy and combination regimens are considered, total benzodiazepine use remains slightly greater in primary care than psychiatry (51% vs. 42%).

Abstract: OBJECTIVES. Narcotic-related adverse drug events are the most common adverse drug events in hospitalized children. Despite multiple published studies describing interventions that decrease adverse drug events from narcotics, large-scale collaborative quality improvement efforts to address narcotic-related adverse drug events in pediatrics have not been described. The purpose of this study was to evaluate collaborative-wide narcotic-related adverse drug event rates after a collection of expert panel– defined best practices was implemented.

Abstract: Approximately seven million people were prescribed a treatment for attention deficit hyperactivity disorder (ADHD) between November, 2006, and October, 2007: 3.8 million ages 0 to 17 years and 3.2 million age 18 years and older. To investigate prescribing trends, we obtained monthly total prescriptions from January, 2003, through October, 2007, for two age groups: patients under 18 years and patients age 18 years and older. The 0 to 17 years age group has demonstrated significant seasonality with total monthly prescription volume dropping between 22 and 29 percent between May and July, depending on the year. In contrast, prescribing trends for adults age 18 years and older have been steadily growing over the time period and do not exhibit any seasonal variation. Interestingly, in July, 2007, for the first time, ADHD total prescriptions for adults were larger than total prescriptions for children.

Abstract: Osteoporosis is a metabolic bone disease resulting from increased bone resorption and characterized by low bone mass that leads to increased bone fragility and risk of fracture, particularly of the hip, spine and wrist. Bone resorption is dependent on receptor activator of NF-kappa B ligand (RANKL), which binds to RANK receptor on preosteoclasts to initiate osteoclastogenesis and maintains osteoclast function and survival. To neutralize the effects of RANKL, the body naturally produces the protein osteoprotegerin (OPG), which acts as a decoy receptor for RANKL and contributes to bone homeostasis. We describe the piecewise development of a three-compartment pharmacokinetic model with both linear and Michaelis–Menten eliminations, and an indirect pharmacodynamic response model to describe the pharmacokinetics and pharmacodynamics, respectively, of the fusion protein, Fc-osteoprotegerin (Fc-OPG), in healthy postmenopausal women. Subsequently, model verification was performed and used to address study design questions via simulation. The model was developed using data from eight cohorts (n = 13 subjects/cohort; Fc-OPG:placebo = 10:3) classified by dose level (0.1, 0.3, 1.0, or 3.0 mg/kg) and route of administration (intravenous [IV] or subcutaneous [SC]). Fc-OPG serum concentrations and urinary N-telopeptide/creatinine ratios (NTX) following both IV and SC administration were available. The model provided an adequate fit to the observed data and physiologically plausible parameter estimates. Model robustness was tested via a posterior predictive check with the model performing well in most cases. Subsequent clinical trial simulations demonstrated that a single 3.0-mg/kg SC dose of Fc-OPG would be expected to produce, at 14 days post-dose, a median NTX percentage change from baseline of −45% (with a 95% prediction interval ranging from −34% to −60%). Lastly, model ruggedness was evaluated using local and global sensitivity analysis methods. In conclusion, the model selection and simulation strategies we applied were rigorous, useful, and easily generalizable.

Abstract: Background: AV-951 inhibits phosphorylation of VEGF receptors (VEGFR)-1, -2, and -3 at picomolar concentrations (IC50 of 0.21, 0.16, and 0.24 nM, respectively) and inhibits c-Kit and PDGFR at 10-times higher concentrations (IC50 of 1.63 and 1.72 nM, respectively). In a dose-escalation study of AV-951 given orally on a 4 week on, 2 week off schedule, the maximum tolerated dose (MTD) was determined to be 1.5 mg/day and clinical activity was observed in renal (RCC), colon, and lung cancers [Proc ASCO 2006;24(18S):2034]. Thereafter, the study was amended to enroll an additional 10 patients at 1.0 mg/day in order to compare the safety profile, pharmacokinetics (PK), effects on tumor blood flow, and antitumor activity across all dose levels. Results: 40 patients (26M/14F), were enrolled at AV-951 doses of 1 (n=16), 1.5 (n=16), and 2.0 mg (n=8). At 2 mg DLTs consisting of grade 3 proteinuria, grade 3 ataxia, and grade 4 intracranial hemorrhage were seen in one patient each. The primary toxicity across all dose levels was hypertension (HTN), as listed in Table 1. HTN was dose-dependent, and could be controlled with standard anti-hypertensive agents. Only two patients, both at 1.5 mg, required dose reduction to 1.0 mg for control of HTN. PK analysis revealed dose dependent drug exposure and peak plasma concentrations. DCE-MRI analysis indicated a decrease in tumor perfusion in selected patients. Among 9 patients with RCC, there were 2 confirmed partial responses at 2.0 mg (n=1) and 1.5 mg (n=1) lasting 128 weeks and 42 weeks, respectively, and 7 patients with stable disease (lasting >12 wks) at 1.0 mg (n=5), 1.5 mg (n=1), and 2.0 mg (n=1). Clinical activity was observed in multiple tumor types. Conclusions: AV-951 could be safely administered at 1.0 and 1.5 mg doses. The primary toxicity was dose-dependent HTN, a biomarker of VEGFR inhibition. Clinical activity was observed across all dose levels. In future combination studies, AV-951 may be administered at a dose of either 1.0 mg or 1.5 mg.

Abstract: In this article, we identify commonly prescribed anticonvulsant medications and characterize central nervous system (CNS) reasons for use. Primary care physicians prescribe 37 percent of all anticonvulsant medications in the US. Psychiatrists are the second highest prescribers with a 19-percent share, and neurologists account for 16 percent of all anticonvulsant medication prescriptions. The top three agents prescribed by psychiatrists are clonazepam, lamotrigine, and divalproex; neurologists most commonly prescribe topiramate, gabapentin, and levetiracetam. Anticonvulsant medications most commonly prescribed by psychiatrists are primarily used for bipolar disorder and anxiety. In contrast, these indications account for less than 10 percent of uses for the top products commonly prescribed by neurologists.

Abstract: Among the challenges facing translational medicine today is the need for greater productivity and safety during the drug development process. To meet this need, practitioners of translational medicine are developing new technologies that can facilitate decision making during the early stages of drug discovery and clinical development. Ex Vivo Metrics™ is an emerging technology that addresses this need by using intact human organs ethically donated for research. After hypothermic storage, the organs are reanimated by blood perfusion, providing physiologically and biochemically stable preparations. In terms of emulating human exposure to drugs, Ex Vivo Metrics is the closest biological system available for clinical trials. Early application of this tool for evaluating drug targeting, efficacy, and toxicity could result in better selection among promising drug candidates, greater drug productivity, and increased safety.

Abstract: DX-k, proposed by Deng and Xu [2003], is a special class of multiple Recursive Generators (MRGs) where all nonzero coefficients of the k-th order recurrence are equal. In particular, a DX-k generator requires only up to four nonzero coefficients in its recurrence equation, hence is very efficient in computation. However, a random number generator with few nonzero coefficients has a drawback that, when the k-dimensional state vector is close to the zero vector, the subsequent numbers generated may stay within a neighborhood of zero for quite many of them before they can break away from this near-zero land, a property apparently not desirable in the sense of randomness. Consequently, two generated sequences using the same DX generator with nearly identical initial state vectors may not depart from each other quickly enough. To avoid the above potential problem, we consider MRGs with very few zero coefficients. To make such generators efficient and portable, we propose selecting the same nonzero value for all coefficients (with at most one exception) in the recurrence equation. With this feature, the proposed generators can be implemented efficiently via a higher-order recurrence of few zero coefficients. Note that the new class of generators is an opposite of the DX generators in terms of the number of nonzero coefficients. Several such generators with the maximum period have been found via computer search and presented in the paper for ready implementation.

Abstract: The Everglades was an almost impenetrable wall of sawgrass “plains” and reptile-infested waters according to the early Spanish and American explorers (Ives 1856; Lodge 1994). Its name may have come from the term “Never Glades” as first used by Vignoles (1823). Originally called Pa-hay-okee (“grassy lake”) by the resident Native Americans, the Everglades was later popularized and put forward as a threatened environment that needed federal protection by Marjory Stoneman Douglas’s seminal 1947 book The Everglades: River of Grass. Her wonderful “river of grass” metaphor has unfortunately led to a simplistic view of the complexities of the Everglades ecosystem, how it functions on the landscape, and how its diversity of communities should be managed to sustain this subtropical wetland (McCally 1999). It is often referred to as the “Everglades marsh or swamp” by local residents, biologists, and engineers; however, it is correctly identified as a fen (Richardson 2000; Keddy 2000; Rydin and Jeglum 2006; Grunwald 2006). In more generic terms, the entire wetland would be referred to as a peatland by wetland ecologists in North America or as a mire by those in Europe. A mire is a wet terrain dominated by living peat-forming plants and is often used in botanical and ecological investigations of vegetation types. “Peatland” is a more universal term used to define a terrain covered by peat, usually to a minimum depth of 30–40 cm. Even if the site is drained, it is still a peatland, but if it loses its original peat-forming plants it is no longer considered a mire (Sjors 1948; Rydin and Jeglum 2006). The terms peatland and mire are therefore not used interchangeably by peatland ecologists in Europe and North America. Here we use “peatland” to generally represent the complex diversity of community types found on peat soils in the Everglades and “fen” in a more strict sense to represent alkaline peat or calcium mineral-based ecosystems found over vast portions of the Everglades landscape. Future detailed research on groundwater flows and geochemistry will be needed to distinguish which specific locations within the Everglades function as true groundwater-influenced fens vs. peatland types with surfaceor rainfall-dominated inputs (discussed later in Sect. 2.5). Thus, the Everglades should not be classified as a swamp because it is not a forest-dominated wetland, and it is not technically a marsh because marshes

Abstract: In combining fluorescence measurements with ligand binding assays, the versatility of the EGFP C-terminally fused to the human mu opioid receptor (EGFP-hMOR) has been exploited to notably improve the expression level of functional G protein-coupled receptors in Drosophila S2 cells. A selected array of efficient optimization approaches is presented herein, ranging from a cell-sorting method, allowing for a substantial enrichment in EGFP-hMOR expressing cells, to the addition of chemical and pharmacological chaperones, significantly enhancing the yield and the activity of the expressed receptors. Consistent with previous studies, significant discrepancies were observed between the total amounts of fluorescent receptors over a limited subpopulation capable of ligand binding, even after expression optimization. Subsequently, membrane isopycnic centrifugation experiments allowed to separate the ligand binding active from the non-active membrane fraction, the latter most probably containing misfolded receptors. Taken together, these results illustrate a coherent set of advantageous productive and preparative methods for the production of GPCRs in the highly valuable Drosophila S2 expression system.

Abstract: We investigated the current practice for treatment of schizophrenia. According to our data, 47 percent of patients with schizophrenia are treated with only antipsychotic medication. An additional 43 percent of patients receive one additional class to supplement their antipsychotic medication, and 10 percent of patients are prescribed two or more classes of drugs in addition to an antipsychotic medication. The most common classes used to supplement antipsychotic medications in the management of schizophrenia include antidepressants (28%), mood stabilizers (18%), agents to treat extrapyramidal symptoms (7%), and sleep aids (5%).

Abstract: The E14 guidelines of the International Conference on Harmonization require that all new drugs that have systemic bioavailability be subjected to a thorough QT/QTc study to look for possible effects on cardiac repolarization.1 Recent publications have discussed various aspects of thorough QTc studies.2,3 The thorough QTc study is designed to detect a mean drug-induced QTc prolongation of >5 ms with an upper bound of the 95% one-sided confidence limits of >10 ms.1,2,3 The E14 guideline has spelled out the procedures to be followed in a thorough QT/QTc study, including choice of subjects, methods of electrocardiogram (ECG) acquisition, details of ECG analysis, and statistical analysis of the study data. Since the measurement of the QT interval is a relatively subjective assessment, the ECGs must be analyzed in a central ECG laboratory by “a few skilled readers.”1 In order to maintain quality in ECG interpretation, the E14 guidelines have two requirements. First, as a measure of the assay sensitivity, the study must include an active control known to prolong the QTc interval.12 Second, a certain percentage of ECGs must be subjected to an inter- and intra-reader variability analysis; these data are submitted to the regulatory authorities along with the study results.1 Clinical Pharmacology & Therapeutics (2008) 83, 3, 489–491.doi:10.1038/sj.clpt.6100481

Abstract: In this article, we investigate the range of treatments prescribed for fibromyalgia. The data suggest that the majority of those treated, 82 percent, receive only one pharmaceutical. An additional 12 percent of patients were prescribed two products and six percent received three products. Pregabalin (Lyrica(R)) monotherapy was the most commonly prescribed regimen (21% of patients) followed by duloxetine (Cymbalta(R)) monotherapy (20%). From a therapeutic class perspective, fibromyalgia patients received antidepressants (46%), antiepileptics (35%), pain therapies (25%), muscle relaxants (8%), and sleep agents (2%). An expert commentary is included.

Abstract: Certain embodiments of the present invention provide clinical site information to clinical trial managers to support clinical trial management. One embodiment is a method for providing information in response to an inquiry. A plurality of site attributes is received. The site attributes can include information regarding the sites that may include clinical trial history, identification, or other site information. Each site attribute includes data elements that are associated with clinical trial sites. A site attribute is identified and a score is determined for each data element of the identified site attribute. An inquiry for clinical trial site information is received. The plurality of data elements are searched to identify at least one clinical trial site based on the inquiry. Information associated with the identified at least one clinical trial site is provided.

Abstract: Recent research on dementia patients suggests that use of antipsychotics may increase risk of hospitalization or death. While bipolar disorder and schizophrenia combine to represent more than 70 percent of atypical antipsychotic uses in younger patients, these same indications represent only 38 percent of product use in patients age 65 and older. The difference between the two age groups is driven primarily by use in cognitive impairment: Dementia and Alzheimer's combine to account for 28 percent of atypical antipsychotic use in older patients. Although ICD-9 coding tends to group patients into less specific diagnoses, we did isolate a small group of approximately 10 percent of patients that were classified based on the presence or absence of behavior disturbances. Eighteen percent of dementia patients without behavioral disturbances received atypical antipsychotics as compared to 66 percent of patients with behavioral disturbances. A discussion of the results is provided.

Abstract: Methods and systems for allocating representatives, such as clinical research associates (CRAs), to sites. One embodiment comprises a method for allocating CRAs to sites by determining for each CRA the first segment travel time from a starting location to a first node associated with a CRA, and the second segment travel time from the first node to a plurality of second nodes, wherein each second node is geographically associated with a site, determining the third segment travel time from each second hub to its corresponding site(s), for each CRA determining the aggregate travel time to each site by adding at least the first, second and third travel segments, for at least some of the CRAs and at least some of the sites, evaluating the aggregate travel times between CRAs to each of the sites, and allocating a CRA to allocate to each site based in part on the travel times.

Abstract: The News story “The bacteria fight back” (Special Section on Drug Resistance, G. Taubes, 18 July, p. [356][1]) clearly describes the current resistance of bacteria to antibiotics and the diminishing pipeline of new products to treat them. However, Louis Rice mistakenly attributes the cause of